U.S. Pat. Nos. 7,314,849 and 7,300,907 describe respectively certain 6-(poly-substituted aryl)-4-aminopicolinate and 2-(poly-substituted aryl)-6-amino-4-pyrimidinecarboxylic acid compounds and their use as herbicides. 2-Fluoro-3-substituted-4-chlorophenylboronic acid and derivatives thereof are useful intermediates for the preparation of these herbicides.
For example, 2-fluoro-3-substituted-4-chlorophenylboronic acid derivatives may be prepared by halogen-metal exchange of 1-bromo-2-fluoro-3-substituted-4-chlorobenzenes with n-butyllithium followed by quenching with a boronic acid ester. As described in U.S. Pat. No. 7,611,647 to Arndt et al., 1-chloro-2-substituted-3-fluorobenzenes may be selectively deprotonated and functionalized in a position adjacent to the fluoro substituent. Selective deprotonation in the position adjacent to the fluoro substituent is achieved by contacting the 1-chloro-2-substituted-3-fluorobenzene starting material with an alkyl lithium compound under anhydrous conditions in an inert organic solvent.
Current methods used to synthesize 4-chloro-2-fluoro-3-methoxyphenylboronic acid (PBA) and derivatives thereof require that the 2-chloro-6-fluoroanisole (2,6-CFA) precursor be cooled to less than about −28° C., and less than about −50° C. in particular embodiments, and treated with butyllithium to form a lithio-2,6-CFA (Li-2,6-CFA) intermediate. This intermediate compound must be kept at a temperature of less than about −50° C. to prevent decomposition, and less than about −28° C. to prevent rapid decomposition, eliminating lithium fluoride to form reactive benzyne species. Producing PBA on a large scale in a batch process, thus, requires cooling of a large volume of solution and the accumulation of a large amount of the reactive intermediate Li-2,6-CFA.